Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :1261
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (1,060 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed1351    
    Printed34    
    Emailed0    
    PDF Downloaded153    
    Comments [Add]    

Recommend this journal

 

  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 316-320
 

Stereotactic body radiation therapy for hepatocellular carcinoma: Experience from a tertiary cancer care center in India


Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, Kerala, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. R Madhavan
Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, Kerala
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_156_17

Rights and Permissions

 » Abstract 

AIM: The aim of this retrospective study is to assess the toxicity and tumor response of stereotactic body radiation therapy (SBRT) protocol for hepatocellular carcinoma (HCC) in our institution. BACKGROUND: Hepatocellular cancer is one of the leading cancers among men in India. In recent years, SBRT has emerged as a promising tool in the treatment of HCC. MATERIALS AND METHODS: Ten patients diagnosed as HCC with Barcelona Clinic Liver Cancer Stage B and C, treated with SBRT technique from January 2013 to December 2016, were included in this study. SBRT was delivered using 6 MV photons with volumetric modulated arc therapy. Acute and late toxicities were graded, and tumor response was assessed using response evaluation criteria in solid tumors criteria. Kaplan–Meier curves were generated for progression-free survival (PFS) and overall survival (OS). RESULTS: The median age was 61.5 (52–69) years. The radiation dose ranged from 35 Gy to 60 Gy. All patients obtained partial response during assessment at 3 months after completion of treatment. The median PFS is 8 months (95% confidence interval [CI] - 5.22–10.77 months). The median OS is 51 months (95% CI - 17.64–65.10 months). The OS at 1 and 2 years is 75% and 57%, respectively. CONCLUSIONS: SBRT is well tolerated by our patients. The 1- and 2-year OS of 75% and 57% is consistent with other prospective and retrospective SBRT studies from the literature.


Keywords: Barcelona clinic liver cancer staging, hepatocellular carcinoma, stereotactic body radiation therapy


How to cite this article:
Madhavan R, Kunher B, Arunlal M, Nair H M, Unnikrishnan U G, Holla R, Makuny D. Stereotactic body radiation therapy for hepatocellular carcinoma: Experience from a tertiary cancer care center in India. Indian J Cancer 2017;54:316-20

How to cite this URL:
Madhavan R, Kunher B, Arunlal M, Nair H M, Unnikrishnan U G, Holla R, Makuny D. Stereotactic body radiation therapy for hepatocellular carcinoma: Experience from a tertiary cancer care center in India. Indian J Cancer [serial online] 2017 [cited 2020 Apr 6];54:316-20. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/316/219543



 » Introduction Top


Liver cancer is one of the leading cancers among men in India. According to the published Indian Council of Medical Research cancer registry data, the age-adjusted incidence of liver cancer in India for men ranges from 0.7 to 7.5 and for women 0.2–2.2/100,000 persons/year.[1] There are numerous staging systems available for hepatocellular carcinoma (HCC). Of these, the Barcelona Clinic Liver Cancer (BCLC) staging has been widely recognized as standard means for assessing the prognosis of patients with HCC.[2],[3] The treatment of hepatocellular cancer depends on the stage of the disease.[4] Early stage patients are potential candidates for curative treatments such as resection, transplantation, or radiofrequency ablation (RFA). Intermediate patients are considered for transarterial chemoembolization (TACE), and advanced cases are offered tyrosine kinase inhibitors such as sorafenib as oral therapy or supportive treatment alone.

In recent years, stereotactic body radiation therapy (SBRT) has emerged as a promising tool in the treatment of HCC. In SBRT technique, high dose of radiation is delivered precisely to small target volume in few fractions. Improved understanding of liver tolerance and advancements in radiation therapy delivery techniques has led to this renewed interest in radiation therapy for liver tumors.[5],[6] Using SBRT, high tumoricidal doses can be given precisely with least possible normal liver tissue damage. Various clinical studies have shown that HCC is a radiosensitive tumor. Unfortunately, the role of SBRT in liver tumors is not yet clearly defined. At present, SBRT is offered to patients whose tumors are not amenable to surgery, ablation, or chemoembolization. Most of the patients who are eligible for transplantation have a considerable waiting time before transplantation. SBRT can be offered during this waiting period as a bridge to transplantation. Various prospective and retrospective small single-institution studies across the world have shown high local control rates for HCC, mostly in the range of 70%–90% at 1–2 years.

Aim

The aim of this retrospective study is to assess the toxicity and tumor response of HCC patients treated with SBRT in our institution.


 » Materials and Methods Top


The patients diagnosed as HCC treated with SBRT technique from January 2013 to December 2016 were included in this study. All cases were discussed in multidisciplinary gastrointestinal tumor board and planned for SBRT. A written consent was obtained from all patients for SBRT. Before starting radiation therapy, pretreatment baseline liver function tests (LFTs) were performed. Child-Pugh class C patients were not offered SBRT. Similarly, BCLC Stage D patients were offered best supportive care. Computed tomography (CT) simulation was performed using Vac-Loc immobilization, and Elekta stereotactic body frame was used. Deep inspiratory breath hold with an active breath coordinator (ABC) was used in all patients to reduce tumor motion during treatment. All patients were given training for ABC for 3 consecutive days before CT simulation. With the help of ABC, contrast-enhanced CT scans were performed in deep inspiratory breath hold.

After CT simulation, the patients are scheduled for gold fiducial placement. Three gold fiducials are placed in the liver around the tumor under ultrasound guidance to identify the tumor during treatment. Ten days after fiducial placement, planning CT scan without contrast was taken using the same Vac-Loc and stereotactic body frame under breath hold. The fiducials in planning CT scan can create artifacts which necessitated a prefiducial contrast CT scan in treatment position. Prefiducial scans were registered, and tumor delineation was performed on contrast CT scan. The contours were reviewed by experienced radiologists. A planning target volume margin of 5 mm was given [Figure 1]. Volumetric modulated arc therapy plans were generated using Monaco treatment planning software [Figure 2]. One full arc and a partial arc were used. Quantitative Analysis of Normal Tissue Effects in the Clinic normal tissue constraints for SBRT were followed. At least 700 cc of normal liver and in cirrhotic cases 1000 cc of the liver should not receive more than 15 Gy. The dose delivered was 35–60 Gy in five fractions. Dose prescription varied depending on the tumor volume and normal liver sparing.
Figure 1: Contouring gross tumor volume on contrast-enhanced computed tomography scan

Click here to view
Figure 2: Isodose distribution of stereotactic body radiation therapy showing low dose spill of 15 Gy

Click here to view


The radiation treatment was delivered using Elekta Synergy linear accelerator. Before starting treatment, a kilovoltage cone beam CT scan was performed under breath hold for anatomical soft tissue matching along with fiducial matching. The necessary couch shifts were applied, and radiation treatment was delivered under deep inspiratory breath hold. A second cone beam CT scan was performed between the two arcs to assess intrafraction treatment motion. The radiation fractions were delivered on consecutive days of a week.

LFT was repeated at the completion of treatment and then 1st, 2nd, and 3rd month of treatment. Acute toxicity was evaluated using common toxicity criteria of the National Cancer Institute. After 3 months, follow-up was done every 3 months for 2 years. The late effects normal tissue/subjective objective management analytic grading system was used for assessing late toxicities. Tumor response was assessed using a triple-phase CT scan 3 months after completion of radiation. Follow-up CT scans were performed every 6 months for 2 years. Tumor response was evaluated using response evaluation criteria in solid tumors criteria. Local failure was defined as an increase in the size of lesion or elevation of tumor markers without evidence of new intrahepatic or extrahepatic lesions.

The statistical analysis was performed using SPSS software version 20. Kaplan–Meier curves were generated for progression-free survival (PFS) and overall survival (OS). Log-rank test was used to assess the correlation of stage and tumor volume with OS and PFS.


 » Results Top


A total of ten patients with HCC were treated at our institution between January 2013 and December 2016. The median age was 61.5 (52–69) years. Five patients belong to BCLC Stage B and the other five patients were in BCLC Stage C. Two patients have Eastern Cooperative Oncology Group (ECOG) performance status I and eight patients had a performance status II. Except three patients, all other patients were cirrhotic. Two patients were of Child-Pugh status B and five patients had Child-Pugh status A cirrhosis. Two patients had undergone prior surgery in the form of nonanatomical resection of liver tumor. One patient had undergone radiofrequency ablation, and another patient had undergone TACE before SBRT.

The median tumor volume was 69.3 cc (24.23 cc–253.12 cc). The segmental distribution and number of lesions were shown in [Table 1]. Five patients had a vascular invasion of tumor in the form of portal vein thrombosis. The radiation dose ranged from 35 Gy to 60 Gy in five fractions. The dosimetric details were listed in [Table 2]. All patients had partial response during an assessment at 3 months after completion of treatment. The median PFS is 8 months (95% confidence interval [CI] - 5.22–10.77 months). The median OS is 51 months (95% CI - 17.64–65.10 months). The Kaplan–Meier curve for PFS and OS is given in [Figure 3] and [Figure 4], respectively. The 1-year local control rate is 25%. The 1- and 2-year OS rate is 87.5% and 56.3%, respectively. On subset analysis, the median PFS is 10 months (95% CI - 5.70–14.29 months) for BCLC Stage B and 7 months (95% CI - 3.79–10.20 months) for BCLC Stage C patients. The OS is 51 months for BCLC Stage B and 14 months for BCLC Stage C patients (P = 0.043). The Kaplan–Meier curve for PFS and OS for BCLC Stage B and C is given in [Figure 5] and [Figure 6], respectively. The 1-year local control rate of BCLC Stage B patients is 40%.
Figure 3: Progression-free survival of patients with hepatocellular carcinoma who received stereotactic body radiation therapy

Click here to view
Figure 4: Overall survival of patients having hepatocellular carcinoma who received stereotactic body radiation therapy

Click here to view
Figure 5: Progression-free survival of Barcelona Clinic Liver Cancer Stage B and Stage C patients who received stereotactic body radiation therapy

Click here to view
Figure 6: Overall survival of hepatocellular carcinoma patients with Barcelona Clinic Liver Cancer Stage B and Stage C treated with stereotactic body radiation therapy

Click here to view
Table 1: Number of lesions and segmental distribution of lesions (patients)

Click here to view
Table 2: Dosimetric details

Click here to view



 » Discussion Top


The BCLC staging system classifies HCC into five stages from Stage 0 (very early) to Stage D (terminal stage) based on the extent of disease, Child-Pugh score, and ECOG performance status. The curative options for very early (Stage 0) and early (Stage A) are resection, liver transplantation, and RFA with a 5-year survival of 50%–70%.[7] Majority of the centers who have facilities for transplantation have a considerable long waiting list. There is a high probability of tumor progression during this waiting period and finally patient can become transplant ineligible. During this period, SBRT can act as a bridge to transplant. In our present study, the median PFS is 8 months which covers the waiting period of transplantation. Similarly, in majority of early stage HCC, percutaneous ablation may not be feasible due to the location of the tumor. The lesions which are close to vessels, subdiaphragmatic position, in proximity to intestines and in caudate lobe are not suitable for percutaneous ablation.[8],[9] Many of these patients may be medically inoperable also due to other comorbidities. SBRT emerges as an ideal option for such patients. Unfortunately, none of the patients in our study were BCLC very early Stage 0 or early Stage A, which are a good prognostic group.

The first-line treatment option for intermediate stage is chemoembolization with a 3-year survival rate of 20%–40%.[10],[11] Five cases in the present study belong to BCLC Stage B and deemed inoperable by surgeons. These cases were not suitable for RFA too due to their location. We offered SBRT to these patients, and their 3-year OS was 75% which is better than chemoembolization. The 1-year local control rate was also good (40%). Thus, our present study had superior results compared to that of TACE mentioned in literature.[12],[13],[14],[15] Five cases in our study belong to advanced Stage C with portal vein invasion. Usually, these cases are managed with oral tyrosine kinase inhibitors such as sorafenib with an OS of 8 months.[16],[17],[18] We treated those patients with SBRT in addition to sorafenib. The median OS and PFS were 14 months and 10 months for BCLC Stage C patients in our retrospective study. Thus, by adding SBRT along with sorafenib, we could improve the OS of our patients.

In the present retrospective study, 1-year and 2-year OS is 75% and 57%, respectively. These results are consistent with previous prospective and retrospective studies mentioned in literature. The various single-institution studies have local control rates in the range of 70%–90% at 1–2 years, but most of the patients were good risk early stage. In the present study, local control rate is 25% at 1 year. This low local control rate is mainly because of the presence of large tumors with advanced stage included in our series. The median tumor volume in our study is 69 cc, which is higher than most of these studies.[19],[20],[21],[22],[23]

Radiation-induced liver disease is a major toxicity after liver irradiation. This is particularly significant in the presence of underlying cirrhosis. This involves anicteric hepatomegaly, ascites, and elevated alkaline phosphatase usually occurring 2–12 months after radiation. Typically high-precision SBRT is considered safe with a chance of liver complications <10%.[24],[25] None of our patients developed any liver complication due to radiotherapy. Another issue in SBRT is the complications after percutaneous fiducial placement. Ohta et al. previously reported low complication rate (2%) after fiducial implantation.[26] Brook et al. also reported that fiducial-related complication in the abdomen and pelvis was 4.3% (8/188).[27] In our series, one patient developed subacute bacterial peritonitis after fiducial placement and he recovered with conservative management.

Limitations of the study

The limitations of this study are retrospective design, small number of patients and patients had various other liver-directed therapies such as resection and chemoembolization before SBRT.


 » Conclusion Top


SBRT is well tolerated by our patients. In BCLC Stage B patients, SBRT results are superior to that of chemoembolization mentioned in literature. The OS is increased by adding SBRT along with sorafenib even in BCLC Stage C patients. The 1- and 2-year OS of 75% and 57% is consistent with prospective and retrospective SBRT studies in the literature. The inferior local control rate in our study is mainly because of the presence of large tumors confirming the importance of tumor volume on local control. Careful treatment planning and sparing of the uninvolved liver is crucial in minimizing the toxicity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
PBCR Reports 2006-2008. Available from: http://www.ncrpindia.org/Reports/PBCR_2006_2008.aspx. [Last accessed on 2017 Jan 25].  Back to cited text no. 1
    
2.
Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329-38.  Back to cited text no. 2
    
3.
Forner A, Rodríguez-Lopez C, Reig M. Natural history and staging for hepatocellular carcinoma. Clin Liver Dis 2012;1:183-5.  Back to cited text no. 3
    
4.
El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011;365:1118-27.  Back to cited text no. 4
[PUBMED]    
5.
Schwarz RE, Abou-Alfa GK, Geschwind JF, Krishnan S, Salem R, Venook AP; American Hepato-Pancreato-Biliary Association; Society of Surgical Oncology; Society for Surgery of the Alimentary Tract. Nonoperative therapies for combined modality treatment of hepatocellular cancer: Expert consensus statement. HPB (Oxford) 2010;12:313-20.  Back to cited text no. 5
[PUBMED]    
6.
Krishnan S, Dawson LA, Seong J, Akine Y, Beddar S, Briere TM, et al. Radiotherapy for hepatocellular carcinoma: An overview. Ann Surg Oncol 2008;15:1015-24.  Back to cited text no. 6
[PUBMED]    
7.
Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-17.  Back to cited text no. 7
[PUBMED]    
8.
Künzli BM, Abitabile P, Maurer CA. Radiofrequency ablation of liver tumors: Actual limitations and potential solutions in the future. World J Hepatol 2011;3:8-14.  Back to cited text no. 8
    
9.
Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio-frequency ablation: Complications encountered in a multicenter study. Radiology 2003;226:441-51.  Back to cited text no. 9
[PUBMED]    
10.
Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet 2002;359:1734-9.  Back to cited text no. 10
    
11.
Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164-71.  Back to cited text no. 11
[PUBMED]    
12.
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003;37:429-42.  Back to cited text no. 12
[PUBMED]    
13.
Oliveri RS, Wetterslev J, Gluud C. Transarterial chemoembolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011;(3):CD004787.  Back to cited text no. 13
    
14.
Ray CE Jr., Haskal ZJ, Geschwind JF, Funaki BS. The use of transarterial chemoembolization in the treatment of unresectable hepatocellular carcinoma: A response to the Cochrane Collaboration review of 2011. J Vasc Interv Radiol 2011;22:1693-6.  Back to cited text no. 14
    
15.
Forner A, Llovet JM, Bruix J. Chemoembolization for intermediate HCC: Is there proof of survival benefit? J Hepatol 2012;56:984-6.  Back to cited text no. 15
[PUBMED]    
16.
Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Subanalyses of a phase III trial. J Hepatol 2012;57:821-9.  Back to cited text no. 16
[PUBMED]    
17.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34.  Back to cited text no. 17
[PUBMED]    
18.
Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III sorafenib Asia-Pacific trial. Eur J Cancer 2012;48:1452-65.  Back to cited text no. 18
[PUBMED]    
19.
Cárdenes HR, Price TR, Perkins SM, Maluccio M, Kwo P, Breen TE, et al. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol 2010;12:218-25.  Back to cited text no. 19
    
20.
Kang JK, Kim MS, Cho CK, Yang KM, Yoo HJ, Kim JH, et al. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 2012;118:5424-31.  Back to cited text no. 20
[PUBMED]    
21.
Choi BO, Jang HS, Kang KM, Lee SW, Kang YN, Chai GY, et al. Fractionated stereotactic radiotherapy in patients with primary hepatocellular carcinoma. Jpn J Clin Oncol 2006;36:154-8.  Back to cited text no. 21
[PUBMED]    
22.
Louis C, Dewas S, Mirabel X, Lacornerie T, Adenis A, Bonodeau F, et al. Stereotactic radiotherapy of hepatocellular carcinoma: Preliminary results. Technol Cancer Res Treat 2010;9:479-87.  Back to cited text no. 22
[PUBMED]    
23.
Andolino DL, Johnson CS, Maluccio M, Kwo P, Tector AJ, Zook J, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e447-53.  Back to cited text no. 23
[PUBMED]    
24.
Tse RV, Hawkins M, Lockwood G, Kim JJ, Cummings B, Knox J, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2008;26:657-64.  Back to cited text no. 24
[PUBMED]    
25.
Pan CC, Kavanagh BD, Dawson LA, Li XA, Das SK, Miften M, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys 2010;76 3 Suppl:S94-100.  Back to cited text no. 25
    
26.
Ohta K, Shimohira M, Sasaki S, Iwata H, Nishikawa H, Ogino H, et al. Transarterial fiducial marker placement for image-guided proton therapy for malignant liver tumors. Cardiovasc Intervent Radiol 2015;38:1288-93.  Back to cited text no. 26
[PUBMED]    
27.
Brook OR, Gourtsoyianni S, Mendiratta-Lala M, Mahadevan A, Siewert B, Sheiman RR. Safety profile and technical success of imaging-guided percutaneous fiducial seed placement with and without core biopsy in the abdomen and pelvis. AJR Am J Roentgenol 2012;198:466-70.  Back to cited text no. 27
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow